Throughout this application, various publications are referenced in parentheses by author and year. Full citations for these references may be found at the end of the specification immediately preceding the sequence listings and the claims. The disclosure of these publications in their entireties are hereby incorporated by reference into this application to describe more fully the art to which this invention pertains.
Biologically active phospholipids are emerging as important intracellular signaling molecules. Among these, lysophosphatidic acid (LPA; 1-acyl-glycerol-3-phosphate) is the simplest glycerophospholipid (Moolenaar, 1994). LPA produces a wide variety of biological responses such as induction of cell proliferation, stimulation of neurite retraction, platelet aggregation, smooth muscle contraction, tumor cell invasion, neurotransmitter release, chloride efflux and chemotaxis (Moolenaar, 1994; Jalink et al., 1994; Van Corven et al., 1989; Tigyi et al., 1994; Tigyi and Miledi, 1992; Jalink et al., 1993; Tokumura et al., 1994; Piazza et al., 1995). LPA is the product of the blood-clotting process and is therefore present in serum. LPA derived from platelets appears to be an important mediator of wound healing and tissue regeneration (Moolenaar, 1995).
The known effects of LPA appear to be mediated by G protein-coupled receptor(s). Specific LPA binding sites have been demonstrated in membranes from 3T3 cells and rat brain with Kd values in the low nanomolar range (Thomson et al., 1994). The actions of LPA are mediated by at least four G protein-mediated signaling pathways: stimulation of phospholipase C and phospholipase D, inhibition of adenylyl cyclase, activation of Ras and Raf/MAP kinase pathway, and tyrosine phosphorylation of focal adhesion proteins (Moolenaar, 1995).
We describe here the isolation and characterization of a novel mammalian LPA receptor, specifically a human LPA receptor. This receptor can serve as a tool for the drug design of novel therapeutic agents for various indications, including cancer (preferably tumor reduction or prevention), platelet aggregation (as an anti-coagulant), vascular restenosis, arthritis (as an anti-inflammatory), wound healing, tissue regeneration (preferably skin and nerve regeneration), blood coagulation, osteoporosis (bone regeneration), and cosmetic uses (preferably the prevention of abnormal growths or scarring or for augmentation).
Independently, the identification of a complementary DNA from Xenopus that encodes a functional high-affinity receptor for LPA has recently been reported (Guo, et al., 1996). Analysis of this receptor revealed that it is a G-protein-coupled-receptor.